Neuroinflammatory Disease Induced by Cells of the Innate Immune System

Glaucia Furtado, Ph.D., and Sergio Lira, Ph.D.

Mount Sinai School of Medicine

Funded in September, 2007: $200000 for 3 years

How Do Innate Immune Cells Induce Inflammatory Disease in the Brain?

Researchers will work to determine whether a specific type of innate immune cell, called a monocyte, and dendritic cell (DC) are involved in initiating inflammatory disease in the brains of laboratory animals.

Inflammation in the central nervous system (CNS, brain, and spinal cord) characterizes a number of diseases, including degenerative Parkinson’s and Alzheimer’s diseases, and autoimmune multiple sclerosis (MS), in which immune cells mistakenly attack the CNS. The researchers hypothesize that innate immune cells are recruited into the CNS in response to trauma, infection, or as a consequence of inappropriate (autoimmune) responses against the CNS. These immune cells, they further hypothesize, produce inflammatory substances that affect the function and viability of neurons and their supportive cells (glia), leading to varying degrees of neurological damage.

The goal of this proposal is to advance our understanding of two key aspects of neuroinflammation: the mechanisms of cell recruitment, and the production of specific molecular effectors. They will determine whether the chemokine CCL2 and its receptor, CCR2, cause the influx of innate immune cells into the CNS, and they will determine whether monocytes and/or DCs, once recruited into the CNS by this chemokine, induce inflammatory CNS disease.

Significance: Determining how inflammatory diseases are induced in the CNS may lead to novel therapies to prevent these disease.

Neuroinflammatory Disease Induced by Cells of the Innate Immune System

Chemokines and chemokine receptors regulate trafficking of innate immune cells into healthy and inflamed tissues. We have used transgenic mice to test the ability of the chemokine CCL2 to promote leukocyte trafficking into the central nervous system (CNS). An increased number of monocytes/DCs was observed in the CNS of animals that expressed CCL2 under the control of the myelin basic promoter. Despite accumulation of cells in the CNS the mice were healthy and did not show signs of neurological disease.

Expansion of monocytes/DCs, DC precursors and NK cells by conditional expression of FLT3 ligand in these animals promoted a neuroinflammatory disease that led to ascending paralysis in 100% of the mice within 9 days. This neuroinflammatory process did not involve T cells, and depletion of phagocytic cells from the periphery decreased disease incidence and severity. These results strongly suggest that the initiation of an autoimmune-like disease can be promoted by cells of the innate immune system.

To define the mechanisms underlying the development of this novel inflammatory model we will analyze the contribution of different innate immune cells to the development of neuroinflammatory disease and we will investigate the mechanism whereby CCL2 and its receptor, CCR2, cause the influx of cells into the CNS.

Glaucia Furtado, Ph.D., and Sergio Lira, Ph.D.

Glaucia C. Furtado, Ph.D., is an Assistant Professor in the Immunology Institute at Mount Sinai School of Medicine. Her research focus on the dynamic of inflammatory cell recruitment to the central nervous system and their role in CNS pathologies. Dr. Furtado received her Ph.D. from the Department of Immunology at University of Sao Paulo, where she studied the molecular interactions between Toxoplasma gondii and host cell. For her postdoctoral studies, Dr. Furtado moved to the University of New York to work with Dr. Juan Lafaille, where she studied the role of regulatory T cells in experimental autoimmune encephalomyelitis.

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